Enantioselective Fashion Research Articles

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

Organocatalytic Enantioselective [8+4] Cycloadditions of Isobenzofulvenes for the Construction of Bicyclo[4.2.1]nonanes

Main observation and conclusionThe [8+4] cycloaddition of indene‐2‐carbaldehydes with indole‐2,3‐quinodimethanes and pyrrolidone‐3,4‐dienes is described, affording indole and pyrrolidone annulated bicyclo[4.2.1]nonanes in a highly peri‐, diastereo‐, and enantioselective fashion in the presence of a secondary amine catalyst. This reaction, which proceeds through catalytically generated isobenzofulvenes, represents the first asymmetric version of high‐order [8+4] cycloaddition.

Stereoselective Access to Spirooxindoles and Bisoxindoles Through Organocatalyzed Asymmetric Divergent Transformations of Isatin-derived MBH Carbonates.

An interesting β-isoquinidine catalyzed divergent reaction was developed to produce either spirocyclopentene oxindoles, spirocyclopentadiene oxindoles or bisoxindoles in a high enantioselective fashion. The utility of this protocol was demonstrated by the versatile transformations of the products. This work not only represents the first highly stereoselective intermolecular catalytic asymmetric allylic alkylation reaction between two isatin-derived MBH carbonate molecules but also constitutes a rare example of isatin-derived MBH carbonate-based enantioselective and α-regioselective [3+2] cycloaddition reactions.

Generation of Axially Chiral Fluoroallenes through a Copper-Catalyzed Enantioselective β-Fluoride Elimination.

Herein we report the copper-catalyzed silylation of propargylic difluorides to generate axially chiral, tetrasubstituted monofluoroallenes in both good yields (27 examples >80%) and enantioselectivities (82-98% ee). Compared to previously reported synthetic routes to axially chiral allenes (ACAs) from prochiral substrates, a mechanistically distinct reaction has been developed: the enantiodiscrimination between enantiotopic fluorides to set an axial stereocenter. DFT calculations and vibrational circular dichroism (VCD) suggest that β-fluoride elimination from an alkenyl copper intermediate likely proceeds through a syn-β-fluoride elimination pathway rather than an anti-elimination pathway. The effects of the C1-symmetric Josiphos-derived ligand on reactivity and enantioselectivity were investigated. Not only does this report showcase that alkenyl copper species (like their alkyl counterparts) can undergo β-fluoride elimination, but this elimination can be achieved in an enantioselective fashion.

α-Keto hydrazones in asymmetric aminocatalysis: reactivity through β-amino aza-dienamine intermediates

α-keto hydrazones activated by a bifunctional amino-thiourea catalyst generate β-amino aza-dienamine intermediates which react with nitroalkenes in highly enantioselective fashion.

Highly Enantioselective Iridium-Catalyzed Hydrogenation of Conjugated Trisubstituted Enones.

Asymmetric hydrogenation of conjugated enones is one of the most efficient and straightforward methods to prepare optically active ketones. In this study, chiral bidentate Ir–N,P complexes were utilized to access these scaffolds for ketones bearing the stereogenic center at both the α- and β-positions. Excellent enantiomeric excesses, of up to 99%, were obtained, accompanied with good to high isolated yields. Challenging dialkyl substituted substrates, which are difficult to hydrogenate with satisfactory chiral induction, were hydrogenated in a highly enantioselective fashion.

Enantioconvergent Amination of Racemic Tertiary C-H Bonds.

Racemization is considered to be an intrinsic stereochemical feature of free radical chemistry as can be seen in traditional radical halogenation reactions of optically active tertiary C-H bonds. If the facile process of radical racemization could be effectively combined with an ensuing step of bond formation in an enantioselective fashion, then it would give rise to deracemizative functionalization of racemic tertiary C-H bonds for stereoselective construction of chiral molecules bearing quaternary stereocenters. As a demonstration of this unique potential in radical chemistry, we herein report that metalloradical catalysis can be successfully applied to devise Co(II)-based catalytic system for enantioconvergent radical amination of racemic tertiary C(sp3)-H bonds. The key to the success of the radical process is the development of Co(II)-based metalloradical catalyst with fitting steric, electronic, and chiral environments of the D2-symmetric chiral amidoporphyrin as the supporting ligand. The existence of optimal reaction temperature is recognized as an important factor in the realization of the enantioconvergent radical process. Supported by an optimized chiral ligand, the Co(II)-based metalloradical system can effectively catalyze the enantioconvergent 1,6-amination of racemic tertiary C(sp3)-H bonds at the optimal temperature, affording chiral α-tertiary amines in excellent yields with high enantiocontrol of the newly created quaternary stereocenters. Systematic studies, including experiments utilizing optically active deuterium-labeled C-H substrates as a model system, shed light on the underlying mechanistic details of this new catalytic process for enantioconvergent radical C-H amination. The remarkable power to create quaternary stereocenters bearing multiple functionalities from ubiquitous C-H bonds, as showcased with stereoselective construction of bicyclic N-heterocycles, opens the door for future synthetic applications of this new radical technology.

Chemo‐ and Stereoselective Synthesis of Fluorinated Amino Alcohols through One‐pot Reactions using Alcohol Dehydrogenases and Amine Transaminases

AbstractA series of amino alcohols have been prepared in a chemo‐, diastereo‐ and enantioselective fashion starting from the corresponding (het)aryl diketones, avoiding tedious chemical protection and deprotection steps. Different alcohol dehydrogenases have been able to selectively reduce the more reactive trifluoroacetyl groups under optimized conditions, while amine transaminases catalyzed the biotransamination of the less hindered acetyl groups. Based on the different reactivity of the acetyl and trifluoroacetyl groups, the design of sequential and concurrent cascades was investigated. The proper selection of the enzymes permits the synthesis of amino alcohol stereoisomers in high to excellent yields (86–>99% conversion) and remarkable stereocontrol (up to >99% de and >99% ee) using an aqueous medium and mild reaction conditions.magnified image

Intramolecular C(sp3 )-H Bond Oxygenation by Transition-Metal Acylnitrenoids.

This study demonstrates for the first time that easily accessible transition‐metal acylnitrenoids can be used for controlled direct C(sp3)‐H oxygenations. Specifically, a ruthenium catalyst activates N‐benzoyloxycarbamates as nitrene precursors towards regioselective intramolecular C−H oxygenations to provide cyclic carbonates, hydroxylated carbamates, or 1,2‐diols. The method can be applied to the chemoselective C−H oxygenation of benzylic, allylic, and propargylic C(sp3)−H bonds. The reaction can be performed in an enantioselective fashion and switched in a catalyst‐controlled fashion between C−H oxygenation and C−H amination. This work provides a new reaction mode for the regiocontrolled and stereocontrolled conversion of C(sp3)‐H into C(sp3)−O bonds.

Intramolecular C(sp3)–H Bond Oxygenation by Transition‐Metal Acylnitrenoids

AbstractThis study demonstrates for the first time that easily accessible transition‐metal acylnitrenoids can be used for controlled direct C(sp3)‐H oxygenations. Specifically, a ruthenium catalyst activates N‐benzoyloxycarbamates as nitrene precursors towards regioselective intramolecular C−H oxygenations to provide cyclic carbonates, hydroxylated carbamates, or 1,2‐diols. The method can be applied to the chemoselective C−H oxygenation of benzylic, allylic, and propargylic C(sp3)−H bonds. The reaction can be performed in an enantioselective fashion and switched in a catalyst‐controlled fashion between C−H oxygenation and C−H amination. This work provides a new reaction mode for the regiocontrolled and stereocontrolled conversion of C(sp3)‐H into C(sp3)−O bonds.

Modular Design of Chiral Conjugate-Base-Stabilized Carboxylic Acids: Catalytic Enantioselective [4 + 2] Cycloadditions of Acetals.

Readily available 1,2-amino alcohols provide the framework for a new generation of chiral carboxylic acid catalysts that rival the acidity of the widely used chiral phosphoric acid catalyst (S)-TRIP. Covalently linked thiourea sites stabilize the carboxylate conjugate bases of these catalysts via anion-binding, an interaction that is largely responsible for the low pKa values. The utility of the new catalysts is illustrated in the context of challenging [4 + 2] cycloadditions of salicylaldehyde-derived acetals with homoallylic and bishomoallylic alcohols, providing polycyclic chromanes in a highly enantioselective fashion.

Catalytic Enantioselective Radical Transformations Enabled by Visible Light.

Visible light has been recognized as an economical and environmentally benign source of energy that enables chemoselective molecular activation of chemical reactions and hence reveal a new horizon for the design and discovery of novel chemical transformations. On the other hand, asymmetric catalysis represents an economic method to satisfy the increasing need for enantioenriched compounds in the chemical and pharmaceutical industries. Therefore, combining visible light photocatalysis with asymmetric catalysis creates a wider range of opportunities for the development of mechanistically unique reaction schemes. However, there arise two main problems like undesirable photochemical background reactions and difficulties in controlling the stereochemistry with highly reactive photochemical intermediates which can pose a serious challenge to the development of asymmetric visible light photocatalysis. In recent years, several methods have been developed to overcome these challenges. This review summarizes the recent advances in visible light-induced enantioselective reactions. We divide our discussion into four categories: Asymmetric photoredox organocatalysis, asymmetric transition metal photoredox catalysis, asymmetric photoredox Lewis acid catalysis and asymmetric photoinduced energy transfer catalysis. Special emphasis has been given to different catalytic activation modes that enable the construction of challenging carbon-carbon and carbon-heteroatom bond in an enantioselective fashion. A brief analysis of substrate scope and limitation as well as reaction mechanism of these reactions has been included.

Highly Enantioselective Synthesis of Propargyl Amide with Vicinal Stereocenters through Ir‐Catalyzed Hydroalkynylation

AbstractChiral propargyl amines are valuable synthetic intermediates for the preparation of biologically active compounds and functionalized amines. Catalytic methods to access propargyl amines containing vicinal stereocenters with high diastereoselectivity are particularly rare. We report an unprecedented strategy for the synthesis of enantioenriched propargyl amines with two stereogenic centres. An iridium complex, ligated by a phosphoramidite ligand, catalyzes the hydroalkynylation of β,β‐disubstituted enamides to afford propargyl amides in a highly regio‐, diastereo‐, and enantioselective fashion. Stereodivergent synthesis of all four possible stereoisomers was achieved using this strategy.

Highly Enantioselective Synthesis of Propargyl Amide with Vicinal Stereocenters through Ir-Catalyzed Hydroalkynylation.

Chiral propargyl amines are valuable synthetic intermediates for the preparation of biologically active compounds and functionalized amines. Catalytic methods to access propargyl amines containing vicinal stereocenters with high diastereoselectivity are particularly rare. We report an unprecedented strategy for the synthesis of enantioenriched propargyl amines with two stereogenic centres. An iridium complex, ligated by a phosphoramidite ligand, catalyzes the hydroalkynylation of β,β-disubstituted enamides to afford propargyl amides in a highly regio-, diastereo-, and enantioselective fashion. Stereodivergent synthesis of all four possible stereoisomers was achieved using this strategy.

Unveiling the Delicate Balance of Steric and Dispersion Interactions in Organocatalysis Using High-Level Computational Methods.

High-level quantum electronic structure calculations are used to provide a deep insight into the mechanism and stereocontrolling factors of two recently developed catalytic asymmetric Diels–Alder (DA) reactions of cinnamate esters with cyclopentadiene. The reactions employ two structurally and electronically very different in situ silylated enantiopure Lewis acid organocatalysts: i.e., binaphthyl-allyl-tetrasulfone (BALT) and imidodiphosphorimidate (IDPi). Each of these catalysts activates only specific substrates in an enantioselective fashion. Emphasis is placed on identifying and quantifying the key noncovalent interactions responsible for the selectivity of these transformations, with the final aim of aiding in the development of designing principles for catalysts with a broader scope. Our results shed light into the mechanism through which the catalyst architecture determines the selectivity of these transformations via a delicate balance of dispersion and steric interactions.

Palladium-Catalyzed Regio-, Enantio-, and Diastereoselective Asymmetric [3 + 2] Cycloaddition Reactions: Synthesis of Chiral Cyclopentyl Phosphonates

The palladium-catalyzed unified approach using in situ-generated Phospha-TMM species to synthesize a diverse array of chiral organophosphorus containing carbo- and heterocyclic compounds in a highly regio-, diastereo- (>20:1 dr), and enantioselective (>99% ee) fashion is being disclosed. The present protocol reveals the potential of the deprotonative phospha-TMM strategy for the synthesis of challenging five-membered carbo- and heterocycles, especially those with spirocyclic entities and quaternary asymmetric stereocenters. The choice of the robust chiral diamidophosphite ligand proved to be very crucial for the desired reactivity in the present transformation. Furthermore, the synthetic utility of the products is demonstrated by multiple transformations such as reductions, oxidations, and alkylations.

Enantioselective formation of quaternary carbon stereocenters in natural product synthesis: a recent update.

Covering: 2013-2018 Natural products bearing quaternary carbon stereocenters have attracted tremendous interest from the synthetic community due to their diverse biological activities and fascinating molecular architectures. However, the construction of these molecules in an enantioselective fashion remains a long-standing challenge because of the lack of efficient asymmetric catalytic methods for installing these motifs. The rapid progress in the development of new-generation efficient chiral catalysts has opened the door for several asymmetric reactions, such as Michael addition, dearomative cyclization, polyene cyclization, α-arylation, cycloaddition, allylation, for the construction of quaternary carbon stereocenters in a highly enantioselective fashion. These asymmetric catalytic methods have greatly facilitated the synthesis of complex natural products with improved output and overall efficiency. In this concise review, we highlight the progress in the last six years in complex natural product synthesis, in which at least one quaternary carbon stereocenter has been constructed via asymmetric catalytic technologies, with particular emphasis on the analysis of the stereochemical model of each enantioselective transformation.

Accessing Enantiopure Epoxides and Sulfoxides: Related Flavin‐Dependent Monooxygenases Provide Reversed Enantioselectivity

AbstractEnantiopure organic compounds are of major importance for the chemical and pharmaceutical industry. Flavin‐dependent group E monooxygenases, composed of monooxygenase and reductase, are known to perform epoxidation of substituted alkenes as well as sulfoxidation in a regio‐ and enantioselective fashion. Group E is divided into styrene monooxygenases (SMO) and indole monooxygenases (IMO). Hitherto mainly SMOs have been characterized. In this study, we assayed 31 monooxygenases from both types, while 23 of which showed activity. They almost exclusively produced (S)‐styrene oxide at high enantiomeric excess with maximum activities of 0.73 μmol min−1 mg−1 (kcat=0.54 s−1). In case of sulfoxidation, we found that the enantioselectivity is contrary between both types. IMOs preferably produce the (S)‐enantiomer while SMOs have a tendency to produce the (R)‐enantiomer. Sequence analysis and molecular docking of substrates allowed identifying fingerprint motives: SMO N46‐V48‐H50‐Y73‐H76‐S96 and IMO S46‐Q48‐M50‐V/I73‐I76‐A96. These form an essential part of the active site while the loop (AS44‐51) interacts with the co‐substrate and other amino acids direct the substrate. The motives clearly distinguish group E monooxygenases and define the enantioselectivity and thus direct biotechnological applications. Two‐hour biotransformations with several sulfides in conjunction with upscale experiments (10 and 100 mg scale) resulted in the identification of promising candidates for the realization of biocatalytic processes.

Metal‐Catalyzed Substrate‐Directed Enantioselective Functionalization of Unactivated Alkenes

Alkenes are versatile compounds that are available on large scales in industry or through chemical synthesis. Selective functionalization of unactivated alkenes in a chemo‐, regio‐, diastereo‐ and enantioselective fashion is a highly sought‐after goal in organic synthesis. Substrate‐directed enantioselective functionalization of unactivated alkenes provides an important strategy to achieve this goal. Using a functional group on the alkene substrate as a native coordinating group, a two‐point binding mode of the substrate to the metal center enables effective control of regio‐, diastereo‐ and enantioselectivities. Through this strategy, a variety of enantioselective functionalization methods have been developed recently. The recent advances in this area are highlighted here.

Stereoconvergent, Redox‐Neutral Access to Tetrahydroquinoxalines through Relay Epoxide Opening/Amination of Alcohols

AbstractWe present an economical catalytic procedure to convert readily available 1,2‐diaminobenzenes and terminal epoxides into valuable 1,2,3,4‐tetrahydroquinoxalines in a highly enantioselective fashion. This procedure operates through relay zinc and iridium catalysis, and achieves redox‐neutral and stereoconvergent production of valuable chiral heterocycles from racemic starting materials with water as the only side product. The use of commercially available reagents and catalysts and a convenient procedure also make this catalytic method attractive for practical application.